Dynamic signature of lymphangiogenesis during acute kidney injury and chronic kidney disease

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes with significant attributable morbidity and mortality. The disturbing trend of increasing incidence and prevalence of these clinical conditions highlights the urgent need for better understanding of the underlying mechanisms that are involved in pathogenesis of these conditions. Lymphangiogenesis and its involvement in various inflammatory conditions is increasingly recognized while its role in AKI and CKD remains to be fully elucidated. Here, we studied lymphangiogenesis in three models of kidney injury. Our results demonstrate that the main ligands for lymphangiogenesis, VEGF-C and VEGF-D, are abundantly present in tubules at baseline conditions and the expression pattern of these ligands is significantly altered following injury. In addition, we show that both of these ligands increase in serum and urine post-injury and suggest that such increment may serve as novel urinary biomarkers of AKI as well as in progression of kidney disease. We also provide evidence that irrespective of the nature of initial insult, lymphangiogenic pathways are rapidly and robustly induced as evidenced by higher expression of lymphatic markers within the kidney.

Lymphatic Vessels Enhancing Adaptive Immunity Deteriorates Renal Inflammation and Renal Fibrosis

“…In addition, VEGF-D is another major promoter of lymphangiogenesis, also depending on VEGFR-3, but its ability to promote lymphangiogenesis is less important than that of VEGF-C. The injury tubules produce a large amount of VEGF-C and VEGF-D during acute kidney injury and chronic kidney disease [49]. Kinashi et al [50] found that connective tissue growth factor (CTGF) is another important determinant of lymphangiogenesis.…”

Heterozygous mutation ofVegfr3decreases renal lymphatics but is dispensable for renal function

“…Renal lymphangiogenesis has been reported to occur in many different clinical scenarios, including cisplatin-induced kidney disease, amongst others (4, 5, 38, 46, 47), and it has generated a logical enthusiasm for targeting the lymphatic system in a wide spectrum of kidney diseases (6, 36, 37, 48). Cisplatin injury did not lead to differences in renal outcomes in Vegfr3 Chy /+ mice.…”

Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases

“…Whereas peritubular capillaries undergo rarefaction, potentially triggering interstitial hypoxia and generating a profibrogenic environment within diseased kidney 59 , renal lymphatics proliferate and sprout, giving rise to new vessels in a process termed lymphangiogenesis 60 . In biopsies of immunoglobulin A nephropathy, focal glomerulosclerosis, lupus, anti-neutrophil cytoplasmic antibody-related glomerulonephritis, diabetic kidney disease (DKD) and chronic interstitial nephritis acquired from patients ranging from moderate CKD to end-stage kidney disease (ESKD), the cross sectional area of lymphatics is significantly greater than in non-diseased kidneys 26,61 ; a finding replicated in multiple murine models of CKD 54,[62][63][64][65][66] .…”

“…However, several questions remain. Structural changes to renal lymphatics are not evident in murine or human AKI 26,66 . However, the possibility that renal lymphatics are altered at the molecular or functional level in acute nephropathy, and whether these can be exploited to prevent the transition from AKI to CKD, warrants further study.…”